4-Phenyl-1-piperazinylalkyl-3-indoles have previously been disclosed in the following patents: Fr. No. 1,551082 (Sterling Drug Inc.--1968); U.S. Pat. No. 3,135,794 (Sterling Drug Inc.--1964); GB No. 944,443 (Sterling Drug Inc.--1963) and in the following papers as well: Med. Pharm. Chem. 5, 932-943 (1962), Arch. intern. Pharmacodyn. 157 (1) 67-89 (1965). These patents and papers have focused on 4-phenyl-1-piperazinylethyl-3-indoles with antihistaminergic, sedative, hypotensive and tranquilizing activity, however, without mentioning of serotonergic activity and the diseases where deficits in this neurotransmitter system are involved. The only butyl derivative included in our invention specifically mentioned in the above patents and papers was 3-[1-(2-methoxyphenyl)-4-piperazinyl]-4-butylindole (Compound 2a).
In the compounds of formula I the preferred compounds are dihydroindoles, 2-indolones and indazoles with R.sup.2 being preferably hydrogen or methyl and R.sup.1 hydrogen, halogen or trifluoromethyl. The aromatic substituent Ar is preferably 2-lower alkoxyphenyl, 1,4-benzodioxan-5-yl, or 2,3-dihydro-7-benzofuranyl.
This invention also includes pharmaceutically acceptable salts of the compounds of Formula I formed with non-toxic organic or inorganic acids. Such salts are easily prepared by methods known to the art.--The base is reacted with either the calculated amount of organic or inorganic acid in an aqueous miscible solvent, such as acetone or ethanol, with isolation of the salt by concentration and cooling or an excess of the acid in aqueous immiscible solvent, such as ethyl ether or chloroform, with the desired salt separating directly.--Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, embonic, succinic, oxalic, bis methylene-salicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tataric, salicylic, citric, glucomic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzene sulfonic and theophylline acetic acids as well as the 8-halotheophyllines, for example 8-bromo-theophylline.--Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. Of course, these salts may also be prepared by the classical method of double decomposition of appropriate salts, which is well-known to the art.
According to the method of the invention, the compounds of Formula I are prepared by
(a) reducing the amide carbonyl of a compound of the formula II ##STR4## wherein R.sup.1, R.sup.2, X and Ar are as previously defined;
(b) alkylating, acylating or arylating a compound of the formula III ##STR5## with an alkyl-, acyl- or phenylhalogenide R.sup.2 X. R.sup.1, X and Ar are as previously defined. Acylation of the NH group with a carboxylic acid chloride with subsequent reduction of the amide also gives compounds o structure I;
(c) alkylating an arylpiperazin ##STR6## with an alkylating reagent of the following formula IV ##STR7## wherein R.sup.1, R.sup.2 and X are as previously defined, while Y is a leaving group as eg. halogen, mesylate or tosylate;
(d) reducing the 2-3 double bond in an indole or indazole derivative of the following formula V ##STR8## wherein R.sup.1, R.sup.2, X and Ar are as previously defined;
(e) oxidizing an indole derivative of the formula VI to an 2-indolone derivative of formula VII ##STR9##
(f) making a ring closure reaction of the hydrazon VIII to the indazole derivative IX ##STR10## whereupon the compound of Formula I formed is isolated as the free base, or a pharmaceutically acceptable acid addition salt thereof, and if desired, separated in individual optical isomers.
The reduction according to method (a) may preferably be carried out in an inert organic solvent such as diethyl ether or tetrahydrofuran in the presence of lithium aluminium hydride at reflux temperature.
Reduction of the 2-3 double bond of indoles or indazoles according to method (d) is conveniently performed by catalytic hydrogenation in an alcohol with platinum or by hydrocarbon with diborane or a diborane precursor such as the trimethylamine or dimethylsulphide complex in tetrahydrofuran or dioxane from 0.degree. C. to reflux temperature, followed by acid catalyzed hydrolysis of the intermediate borane derivative.
Alkylation of an arylpiperazine according to method (c) is conveniently performed in an inert organic solvent such as a suitably boiling alcohol or ketone, preferably in the presence of a base (potassium carbonate or triethylamine) at reflux temperature.
1-Arylpiperazines are either commercially available or may be prepared according to the methods in Martin et al. J. Med. Chem., 32 1052-1056 (1989).
3Indolebutyric acids are convenient starting materials for the preparation of indolebutyric acid amides (formula, II, X.dbd.CH) and for alkylating indolebutyl derivatives (formula, IV, X.dbd.CH). The butyric acids are prepared according to DE No. 3421,641 A1 or HUN.PAT. No. 187 127.
The carboxylic acids are further reacted according to the following reaction scheme: ##STR11##
Hydrazones of the general Formula VIII are conveniently obtained according to the following reaction procedure: ##STR12##
The methods of the invention shall in the following be illustrated by some examples which, however, may not be construed as limiting: